The purpose of this study was to develop a swine model for the in vivo preclinical evaluation of mechanical heart valves and to assess the ability of this model to identify mechanical heart valve design features that result in valve-related thrombosis. Twenty-two swine underwent mitral valve replacement using three different bileaflet mechanical valve designs (i.e. St. Jude Medical, Carbomedics, Medtronic Parallel). Each animal was placed in an anticoagulation protocol (Group I-International Normalized Ratio (INR) 3.0-3.5; Group II- INR 2.0-2.5, and Group III-no anticoagulation) and followed for up to 20 weeks. Terminal studies were performed on all animals surviving for more than thirty days. Twenty-one animals survived the immediate postoperative period. Four of 6 Group I animals died with hemorrhagic (large wound hematoma; hemopericardium) complications early in the study. In the two long-term (61 and 89 days) survivors INRs of 3.0 to 3.5 were never achieved (61 days-mean INR, 2.0-1.03; range, 0.8-5.4; 89 days-mean INR, 1.92-1.34; range, 1.0-7.9). Pathologic analysis of the explants from Group I survivors revealed minimally obstructive fibrous sheathing on the inflow orifice without restriction of bileaflet motion (61 and 89 days), and two large perivalvular defects (61 days). Six of 7 Group II animals died of early hemorrhagic complications (hemopericardium) (mean INR, 2.32-1.84; range, 0.8-8.2). Vegetations resulting in obstruction of both sides of the valve orifice and restriction of bileaflet motion were observed in a Group II survivor (mean INR, 2.33-1.58; range, 0.9-7.0). Group III animals (N=8) survived for a mean of 60-160 days (range 1-177 days). Fibrous sheathing was present on all explanted valves and organized thrombi were observed in six valves. Orifice obstruction (7 of 8 valves) and restriction of bileaflet motion (3 of 8 valves) were also observed. The use of swine as preclinical models for the evaluation of safety and performance of mechanical heart valves is limited by: 1) difficulty in maintaining safe levels of anticoagulation with warfarin, resulting in a high incidence of hemorrhagic complications; 2) marked fibrous sheathing formation and associated thrombosis; and 3) an increased incidence of paravalvular defects.